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Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results.
Brastianos, PK, Kim, AE, Giobbie-Hurder, A, Lee, EQ, Lin, NU, Overmoyer, B, Wen, PY, Nayak, L, Cohen, JV, Dietrich, J, et al
Nature medicine. 2023;(7):1728-1737
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Abstract
Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31-54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5-8.7 months) across both cohorts, 6.5 months (90% CI: 4.5-18.7 months) for cohort A and 8.1 months (90% CI: 5.3-9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41-64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585.
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström, M, Diekmann, L, Bonfiglio, F, Hadizadeh, F, Kuech, EM, von Köckritz-Blickwede, M, Thingholm, LB, Zheng, T, Assadi, G, Dierks, C, et al
Gut. 2018;67(2):263-270
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Plain language summary
Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder which results in a lower ability to digest certain sugars, resulting in diarrhoea, abdominal pain and bloating, which are also common symptoms of Irritable Bowel Syndrome (IBS). The objective of this study was to test sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. The researchers looked at genetics in several populations with and without IBS. The researchers found that genetic mutations are associated with a 35% reduction in the activity of the SI enzymes. CSID mutations were almost twice as common in IBS patients than healthy controls. The genetic variant 15Phe was associated with diarrhoea, stool frequency and changes in the gut bacteria. The authors concluded that people with SI gene variants associated with reduced enzyme activity are more at risk of IBS. Genetic screening could help to identify individuals at increased risk of IBS, and may lead to more targeted treatment for some people with IBS.
Abstract
OBJECTIVE IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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Chronic thromboembolic pulmonary hypertension (CTEPH) - potential role of multidetector-row CT (MD-CT) and MR imaging in the diagnosis and differential diagnosis of the disease.
Wirth, G, Brüggemann, K, Bostel, T, Mayer, E, Düber, C, Kreitner, KF
RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 2014;(8):751-61
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) can be defined as pulmonary hypertension (resting mean pulmonary arterial pressure of 25 mm Hg or more determined at right heart catheterization) with persistent pulmonary perfusion defects. It is a rare, but underdiagnosed disease with estimated incidences ranging from 0.5% to 3.8% of patients after an acute pulmonary embolism (PE), and in up to 10% of those with a history of recurrent PE. CTEPH is the only form of pulmonary hypertension that can be surgically treated leading to normalization of pulmonary hemodynamics and exercise capacity in the vast majority of patients. The challenges for imaging in patients with suspected CTEPH are fourfold: the imaging modality should have a high diagnostic accuracy with regard to the presence of CTEPH and allow for differential diagnosis. It should enable detection of patients suitable for PEA with great certainty, and allow for quantification of PH by measuring pulmonary hemodynamics (mPAP and PVR), and finally, it can be used for therapy monitoring. This overview tries to elucidate the potential role of ECG-gated multidetector CT pulmonary angiography (MD-CTPA) and MR imaging, and summarizes the most important results that have been achieved so far. Generally speaking, ECG-gated MD-CTPA is superior to MR in the assessment of parenchymal and vascular pathologies of the lung, and allows for the assessment of cardiac structures. The implementation of iodine maps as a surrogate for lung perfusion enables functional assessment of lung perfusion by CT. MR imaging is the reference standard for the assessment of right heart function and lung perfusion, the latter delineating typical wedge-shaped perfusion defects in patients with CTEPH. New developments show that with MR techniques, an estimation of hemodynamic parameters like mean pulmonary arterial pressure and pulmonary vascular resistance will be possible. CT and MR imaging should be considered as complementary investigations providing comprehensive information in patients with CTEPH.
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Gastrointestinal well-being in subjects reporting mild gastrointestinal discomfort: characteristics and properties of a global assessment measure.
Guyonnet, D, Naliboff, B, Rondeau, P, Mayer, E, Chassany, O
The British journal of nutrition. 2013;(7):1263-71
Abstract
There is a lack of recognised markers for measuring gastrointestinal (GI) well-being and digestive symptoms in the general population. The aim of the present study was to demonstrate construct validity of a global assessment tool of GI well-being. In this randomised double-blind study, 197 adult women consumed either a probiotic fermented milk or a control dairy product daily during 4 weeks. GI well-being was assessed weekly using a single question and subjects indicated whether their GI well-being remained the same, improved or worsened compared with the baseline period. Responders for GI well-being were subjects reporting improvement for at least 2 weeks of the 4 weeks of intervention. Frequency of individual digestive symptoms was assessed weekly. Health-related quality of life (HRQoL) was measured at baseline and at the end of the study. Subjects reporting improvement of their GI well-being had a significantly (P<0·05) lower frequency of combined digestive symptoms than individuals with no change, whereas subjects with worsened GI well-being had a significantly (P<0·05) higher digestive symptom frequency. Number of weeks with reported GI well-being improvement was significantly (P<0·05) correlated with the decrease in digestive symptoms (r 0·58) and the HRQoL digestive comfort dimension (r 0·47). When compared with non-responders, responders had significantly (P<0·0001) fewer average digestive symptoms and higher scores on digestive comfort of the HRQoL questionnaire. The data provide construct validity for a single-item questionnaire as a measure of GI well-being improvement. These data support the use of this questionnaire as an end point for nutritional intervention in the general population.
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Allergic sensitization in kidney-transplanted patients prevails under tacrolimus treatment.
Gruber, S, Tiringer, K, Dehlink, E, Eiwegger, T, Mayer, E, Konstantin, H, Kikic, Z, Graf, A, Szépfalusi, Z
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2011;(8):1125-32
Abstract
BACKGROUND Type I allergies have repeatedly been reported after solid organ transplantation despite T cell-targeted immunosuppressive therapy. A causal relationship with tacrolimus has been proposed. OBJECTIVE The present study directly compared the occurrence of allergic sensitization and disease under tacrolimus- vs. cyclosporin A-based immunosuppressive therapy. METHODS The prevalences of IgE-mediated sensitization and allergy were assessed in a cross-sectional study of kidney-transplanted adults receiving tacrolimus (n = 100) or cyclosporin A (n = 100). METHODS included a standardized questionnaire, skin prick test and measurement of total and specific IgE against common nutritive and inhalant allergens. Results The prevalence of sensitization was significantly higher in the tacrolimus- than in the cyclosporin A-treated group (34%, n = 34, vs. 20%, n = 20; P = 0.026). The rate of clinically relevant allergy in patients receiving tacrolimus was twice that in patients receiving cyclosporin A (15%, n = 15, vs. 8%, n = 8; P = 0.12). No other factor (age, serum drug level, concomitant immunosuppressive medication, time since transplantation, underlying disease) was found to have an influence on sensitization or allergy prevalence (logistic regression). CONCLUSION AND CLINICAL RELEVANCE Our results suggest that post-transplant immunosuppression with tacrolimus is associated with an increased occurrence of IgE-mediated sensitization and probably manifestation of allergic disease, which has to be treated specifically despite immunosuppressive therapy.
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Hydration of hydroxypyrrole influences binding of ImHpPyPy-beta-Dp polyamide to DNA.
Wellenzohn, B, Loferer, MJ, Trieb, M, Rauch, C, Winger, RH, Mayer, E, Liedl, KR
Journal of the American Chemical Society. 2003;(4):1088-95
Abstract
Ligands which are able to recognize DNA sequence specifically are of fundamental interest as transcription controlling drugs. Recently a polyamide ligand was developed (ImHpPyPy-beta-Dp) which differentiates in a dimeric arrangement between all four possible base pair steps in the minor groove. This is a landmark for the design of DNA binding drugs because it was believed that such a recognition could only be possible in the major groove of DNA. Although the OH groups of the hydroxypyrrole (Hp) moieties of the ligands are responsible for this sequence discrimination, experiments showed that this OH group also reduces the absolute binding constant. We performed a free energy calculation by means of thermodynamic integration in order to find out the influence of this single hydroxyl on DNA binding. In our simulation, we found that the hydroxyl group reduces binding by about 1.3 kcal/mol, which is in excellent agreement with the experimentally determined value of 1.2 kcal/mol. In further MD simulations, the structural reasons for this reduction was estimated. The results of these simulations qualitatively agree with the X-ray structures, but in contrast, in the simulations both (ImHpPyPy-beta-Dp and ImPyPyPy-beta-Dp) ligand-DNA (d(CCAGTACTGG)(2)) complexes exhibit only slight structural differences. This is consistent with a recently published second pair of similar polyamide DNA crystal structures. Thus, we believe that the explanations resulting from the X-ray structures must be modified. We attribute the large structural differences between the two polyamide DNA complexes to a buffer molecule which binds only in the case of the ImHpPyPy-beta-Dp-DNA complex at the region of interest. We propose that the differential hydration of both ligands in the unbound state is responsible for the reduction of the binding constant. Additionally, we suggest an indirect readout of DNA, because of a lengthening of the Watson-Crick base pairs, which possibly contributes to the differentiation between T.A, A.T from G.C, C.G base pairs.
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Indirect readout of the trp-repressor-operator complex by B-DNA's backbone conformation transitions.
Wellenzohn, B, Flader, W, Winger, RH, Hallbrucker, A, Mayer, E, Liedl, KR
Biochemistry. 2002;(12):4088-95
Abstract
Although the trp-repressor-operator complex is one of the best studied transcriptional controlling systems, some questions regarding the specific recognition of the operator by the repressor remain. We performed a 2.35 ns long molecular dynamics simulation to clarify the influence of the two B-DNA backbone conformational substates B(I) and B(II) on complexation. The trp-repressor-operator is an ideal biological system for this study because experimental results have already figured out that the interaction between the internucleotide phosphates and the protein is essential for the formation of the high affinity complex. Our simulation supports these results, but more important it shows a strong correlation between the B(I)/B(II) phosphate substate and the number of interactions with this phosphate. In particular the B(I) <==> B(II) transitions occur synchronous to hydrogen bond breaking or formation. To the best of our knowledge, this was observed for the first time. Thus, we conclude that the sequence specific B(I)/B(II) behavior contributes via indirect readout to sequence specific recognition. These results have implication for the design of transcription-controlling drugs in view of the recently published influence of minor groove binders on the B(I)/B(II) pattern. The simulation also agrees with crystallographically observed hydration sites. This is consistent with experimental results and indicates the correctness of the model used.